Results

Flow of study selection and descriptives

The flow of study selection is shown in Figure 1 (to be updated and included).

The table of included studies is presented in Table 1.

Name Title ID Sponsor Design Population Intervention Sample size Objectives Start date Completion date Completion year Status Available data
Fowler (2015) A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure NA Hoffmann-La Roche DB-RCT; single ascending dose (phase I) Men 18-45 years RO5263397 (1mg to 125mg); Placebo 49 Tolerability, pharmacokinetics NA NA 2015 completed None
JapicCTI-194581 (2019) A Phase I Single-Ascending Dose and Multiple-Ascending Dose Study of RO6889450 in Healthy Japanese Male JapicCTI-194581 Hoffmann-La Roche DB-RCT; single and multiple ascending dose (phase I) Men 20-45 years Ralmitaront; Placebo 64 Tolerability, pharmacokinetics 27.01.19 23.10.19 2019 completed None
NCT02699372 (2016) The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of RO6889450 in Healthy Volunteers BP30134, NCT02699372 Hoffmann-La Roche DB-RCT; single and multiple ascending dose up to 2 weeks (phase I) Men/women 18-45 years Ralmitaront (5 mg to 450mg); Placebo 164 Tolerability, pharmacokinetics 21.03.16 14.04.17 2017 completed None
NCT04512066 (2020) A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder BP41743, NCT04512066, JPRN-jRCT2031200288 Hoffmann-La Roche DB-RCT; 8 weeks (up to 48 weeks extension) (phase II) Men/women 18-45 years with schizophrenia or schizoaffective disorder (acute, DSM-5) Ralmitaront 45mg/d; Ralmitaront 150mg/d; Risperidone 4mg/d; Placebo 287 Efficacy (acute), tolerability 08.09.20 21.06.22 2022 completed Efficacy, dropouts, side-effects
NCT03669640 (2018) A Study to Assess the Effects of RO6889450 (Ralmitaront) in Participants With Schizophrenia or Schizoaffective Disorder and Negative Symptoms BP40283, NCT03669640, EUCTR2020-004752-16, JPRN-jRCT2031200287 Hoffmann-La Roche DB-RCT; 12 weeks (phase II) Men/women 18-55 years with schizophrenia or schizoaffective (predominant negative symptoms, DSM-5) Part A: Ralmitaront; placebo (monotherapy)
Part B: Ralmitaront low or high dose; placebo (add-on to current antipsychotics) 128 Efficacy (negative symptoms), tolerability 04.12.18 08.05.23 2023 completed None
DA801002 (in Galluppi 2021) Population pharmacokinetic analysis of ulotaront in subjects with schizophrenia DA801002 Sunovion/Sumitomo SB-RCT single ascending dose (phase I) Men >18 years Ulotaront (25mg to 50mg); Placebo 16 Pharmacokinetics NA NA 2021 completed None
SEP361-101 (in Galluppi 2021 and Chen 2022) A sensitive LC-MS/MS method for simultaneous quantification of ulotaront and its N-desmethyl metabolite in human plasma and application to a clinical study SEP361-101 Sunovion/Sumitomo SB-RCT; single ascending dose (phase I) Men >18 years Ulotaront (5mg to 125mg); Placebo 52 Pharmacokinetics NA NA 2021 completed None
Hopkins (2021) Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans SEP361-103 Sunovion/Sumitomo DB-RCT two-period crossover; single dose (phase I) Men 18-35 years Cohort 1: Ulotaront 10mg; Placebo
Cohort 2: Ulotaront 50mg; Placebo 24 Sleep parameters, pharmacokinetics NA NA 2021 completed Dropouts, side-effects
Isaacson (2023) Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study. SEP361-203, NCT02969369 Sunovion/Sumitomo DB-RCT; 6 weeks (with open label extension) (phase 2) Men/women ≥55 years with Parkinson’s disease psychosis (acute) Ulotaront 20-75mg/d; Placebo 39 Efficacy (acute), safety 21.11.16 05.07.23 2023 completed Efficacy, dropouts, side-effects
NCT04072354 (2019) A Clinical Trial to Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia SEP361-301, NCT04072354, EUCTR2019-000470-36 Sunovion/Sumitomo DB-RCT; 6 weeks (phase 3) Men/women 13-17 and 18-65 years with schizophrenia (acute, DSM-5) Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo 463 Efficacy (acute), tolerability 11.09.19 08.06.23 2023 completed Efficacy, dropouts
Koblan (2020) A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia SEP361-201, NCT02969382, EUCTR2016-001555-41 Sunovion/Sumitomo DB-RCT; 4 weeks (with open label extension) (phase 2) Men/women 18-40 years with schizophrenia (acute, DSM-5) Ulotaront (50-75mg/d); Placebo 245 Efficacy (acute), tolerability 05.12.16 31.07.18 2018 completed Efficacy, dropouts, side-effects
Perini (2023) Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy SEP361-104, NCT01972711 Sunovion/Sumitomo DB-RCT; single dose (phase 1) Men/women 18-45 years (high or low levels of schizotypy) Ulotaront 50mg; Amisulpride 400mg; Placebo 105 fMRI 41699 42186 2015 completed Dropouts, side-effects
NCT01940159 (2013) A Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Male and Female Subjects With Schizophrenia SEP361-105, NCT01940159 Sunovion/Sumitomo SB-RCT; single ascending dose (phase 1) Men/women 18-50 years with schizophrenia (stable, DSM-IV-TR) Ulotaront (50mg to 150mg); Placebo 48 Tolerability, pharmacokinetics 41334 41730 2014 completed None
Szabo (2023) A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. SEP361-108 , NCT05015673 Sunovion/Sumitomo DB-RCT three-period crossover; 2 weeks (phase 1) Men/women 18-55 years with narcolepsy/cataplexy Ulotaront 25mg; Ulotaront 50mg; Placebo 18 Sleep parameters, pharmacokinetics, tolerability 05.06.14 26.05.15 2015 completed Dropouts, side-effects
Koblan (2016) A phase 1 open label safety and tolerability study of SEP-363856, a novel NON-D2 mechanism of action molecule, in patients with schizophrenia SEP361-106, NCT01994473 Sunovion/Sumitomo SB-RCT; multiple ascending dose for 1 week (including open label extension) (phase 1) Men/women 18-55 years with schizophrenia (stable, DSM-IV-TR) Ulotaront (10mg/d to 100mg/d); Placebo 48 Tolerability, pharmacokinetics 41334 41974 2014 completed None
NCT04092686 (2019) A Clinical Trial That Will Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia SEP361-302, NCT04092686, EUCTR2019-000697-37 Sunovion/Sumitomo DB-RCT; 6 weeks (phase 3) Men/women 18-65 years with schizophrenia (acute, DSM-5) Ulotaront 75mg/d; Ulotaront 100mg/d; Placebo 462 Efficacy (acute), tolerability 30.09.19 08.09.23 2023 completed Efficacy, dropouts
NCT04325737 (2020) Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Japanese Male and Female Subjects With Schizophrenia DA801102, NCT04325737, jRCT2080225100 Sunovion/Sumitomo DB-RCT; 2 weeks (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Cohort 1: Ulotaront (50mg/d to 100mg/d); Placebo
Cohort 2: Ulotaront (25mg/d to 100mg/d); Placebo 13 Tolerability, pharmacokinetics 31.03.20 07.08.20 2020 completed None
Tsukada (2023) A randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia. SEP361-114, NCT04369391 Sunovion/Sumitomo DB-RCT three-period crossover; single dose (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront 150mg; Placebo; Moxifloxacin 400mg (ineligible for the review) 68 QTc interval, tolerability, pharmacokinetics 18.06.20 10.11.20 2020 completed Dropouts, side-effects
NCT04115319 (2019) A Study of the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia. SEP361-304, NCT04115319 , EUCTR2019-002259-40 Sunovion/Sumitomo DB-RCT; 52 weeks (phase 3) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront 50-100mg/d; Quetiapine XR 400-800mg/d 475 Efficacy (maintenance), tolerability 15.11.19 30.12.22 2022 completed None
NCT05729373 (2023) A Clinical Study That Will Meaure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anixety Disorder SEP361-226, NCT05729373, EUCTR2022-502077-42-00 Sunovion/Sumitomo DB-RCT; 8 weeks (phase 2/3) Men/women 18-65 years with GAD (acute, DSM-5) Ulotaront (50-75mg/d); Placebo 464 Efficacy (GAD), tolerability 08.03.23 08.02.25 NA ongoing None
NCT05593029 (2022) A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder 382-201-00001, NCT05593029 Sunovion/Sumitomo DB-RCT; 14 weeks (phase 2/3) Men/women 18-65 years with MDD (acute, DSM-5) Ulotaront; Placebo (add-on to antidepressants) 900 Efficacy (MDD), tolerability 09.11.22 45778 NA ongoing None
NCT04825860 (2021) A Clinical Trial to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic People With Schizophrenia, Followed by an Open-label Extension Phase DA801201, NCT04825860, jRCT2071210003 Sunovion/Sumitomo DB-RCT; 6 weeks (and open label extension) (phase 2/3) Men/women 18-65 years with schizophrenia (acute, DSM-5) Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo 480 Efficacy (acute), tolerability 29.03.21 30.06.25 NA ongoing None
NCT05848700 (2023) A Clinical Study to Learn if SEP-363856 Has Physical Dependence in Adults With Schizophrenia SEP361-121, NCT05848700 Sunovion/Sumitomo DB-RCT; 10 weeks (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront continuation; Ulotaront discontinuation (switch to placebo) 60 Physical dependence, pharmacokinetics 21.06.23 23.02.24 NA ongoing None
NCT05542264 (2022) A Clinical Study That Will Assess the Effect of SEP-363856 or Prior Antipsychotic (PA) Standard of Care on Body-weight Associated Parameters in Subjects With Schizophrenia SEP361-122, NCT05542264 Sunovion/Sumitomo DB-RCT; 2 weeks (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront; Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) 60 Metabolic parameters 15.11.22 23.10.23 NA ongoing None
NCT05402111 (2022) A Clinical Study That Will Assess How Food Moves Through the Stomach and Effects Blood Glucose Levels in Subjects With Schizophrenia Taking SEP-363856 or and Prior Antipsychotic (PA) Standard SEP361-124, NCT05402111 (2022) Sunovion/Sumitomo Open RCT two-period crossover; single dose (phase 1) Men/women 18-65 years with schizophrenia (stable, DSM-5) Ulotaront (25mg to 50mg); Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) 36 Pharmacokinetics, metabolic parameters 13.06.22 13.07.23 NA ongoing None

Table 1 Table of included studies.

Acute psychosis: There were five trials that provived data for the timepoint of 3-13 weeks: 1) One study on ralmitaront, i.e., NCT04512066 examining the comparisons of ralmitaront vs. placebo or risperidone in adults with schizophrenia or schizoaffective disorder. 2) Four studies on ulotaront, i.e., Isaacson 2023 in adults with Parkinson disease psychosis, and Koblan 2020, NCT04072354 and NCT04092686 in adults with schizophrenia. Unavailable trials: 1) The study NCT04072354 (ulotaront vs. placebo) consisted of adolescent and adult parts, but data for the former were not found and the status is unclear. 2) One study (NCT04825860) examining ulotaront vs. placebo in adults with schizophrenia is currently ongoing.

Clinically stable patients with psychosis: There were data from one trial that provided data for the timepoint 1 day - 2 weeks: Tsukada 2023 that was a single dose crossover trial examining mainly the effects of ulotaront vs. placebo or moxifloxacin (not relevant for this analysis) on QTc interval prolongation in stable patients with schizophrenia. Unavailable trials: 1) NCT04115319 examining the long-term efficacy and safety of ulotaront vs. quetiapine in clinically stable patients with schizophrenia (recently completed), 2) Seven trials examining single or multiple doses of ulotaront focusing on pharmacokinetics or safety (e.g., physical dependence or metabolic side-effects) (completed and unpublished: NCT01940159, Koblan 2016, NCT04325737, NCT04865835; ongoing NCT05848700, NCT05542264, NCT05402111). No study examining ralmitaront was found for clinically stable psychosis.

Other patient subgroups: No study with available data was found for other patient subgroup such as first-episode and predominant negative symptoms. Unavailable trials: One study examined ralmitaront vs. placebo (as monotherapy or add-on to current antipsychotic treatment) in patients with schizophrenia or schizoaffective disroder and predominant negative symptoms (NCT03669640), which was reported to be failed but no data were available to be synthesized.

Other mental health conditions: There was one crossover study examining ulotaront vs. placebo in patients with narcolepsy-cataplexy that provided safety data for the timepoint of 1 day - 2 weeks (Szabo 2023). Unavailable trials: Two trials are currently ongoing and examine the efficacy of ulotaront compared to placebo in patients with generalized anxiety disorder (NCT05729373) and major depression (NCT05593029). None of the trials examined ralmitaront in patients with other mental health conditions.

Healthy volunteers: There were four trials examining ulotaront in healthy volunteers that provided safety data for the timepoint of 1 day - 2 weeks: 1) One trial examining the effects of a single dose of ulotaront on fMRI compared to placebo or amisulpride in participants with low or high levels of schizotypy (Perini 2023; safety data were used, fMRI data deeemed not relevant for the first iteration of the review), 2) Two crossover trials examining the pharmacokinetics of single doses of ulotaront vs. placebo in healthy volunteers (SEP361-111 and SEP361-117 as reported in Chen 2023), and 3) One crossover trial examining the effects of single administration of two doses of ulotaront vs. placebo on sleep parameters in healthy volunteers (Hopkin 2021, only safety data were used in the first iteration, and data from the low dose were not used due to the crossover design of the study). Unavailable trials: 1) Three studies examining the pharmacokinetcis and safety of ralmitaront in healthy volunteers (Fowler 2015, JapicCTI-194581, NCT02699372), 2) Two studies examining the pharmacokinetics of ulotaront in healthy volunteers (SEP361-101 , DA801002).

Risk of bias assessment

Risk of bias was evaluated using the RoB2 tool for the primary outcome, i.e., overall symptoms. There were available data only for the primary timepoint (3 weeks - 13 weeks) in acutely ill patients with Parkinson disease psychosis (Isaacson 2023) and schizophrenia spectrum disorder (Koblan 2020, NCT04092686, NCT04072354, NCT04512066).

The risk of bias assessment per domain and study is reported in Figure 1.

Figure 1 Risk of bias for overall symptoms

Three of the studies had an overall high risk of bias due to high risk of bias in missing outcome data (either due to high dropout rates Issacson 2023 or due to the non-reporting of dropouts in the two unpublished studies NCT04072354 and NCT04092686). The other two studies (Koblan 2020 and NCT03669640) had some concerns overall due to some concerns in the domain of missing outcome data (high dropout rates with unclear impact on the findings).

Comparison 1: TAAR1 agonist vs placebo

Primary outcome: Overall symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks (primary timepoint)

Meta-analysis of variance was not conducted because 1) SDs were not reported in two studies (NCT04072354 and NCT04092686) and thus they were imputed, 2) SD of change was reported in one of the studies on schizophrenia (Koblan 2020), while SD of endpoint scores in another studt (NCT04512066).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Positive symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished acute studies on ulotaront (i.e., NCT04072354, NCT04092686).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Negative symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished acute studies on ulotaront (i.e., NCT04072354, NCT04092686).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Depressive symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished acute studies on ulotaront (i.e., NCT04072354, NCT04092686).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Cognitive symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Data were available only from the study on Parkinson disease psychosis (i.e., Isaachson 2023). No data from RCT on schizophrenia.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Quality of life

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Functioning

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Response to treatment

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Imputations of responders were required in the unpublished ulotaront studies (i.e., NCT04072354, NCT04092686); cutoff of 50% change from baseline was used.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Relapse

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Dropouts due to any reason

Timepoint 1: 1 day - 2 weeks

Correlation was assumed 0 for the crossover study (Hopkins 2021)

Timepoint 2: 3 weeks - 13 weeks

No data were available from the unpublished ulotaront studies (i.e., NCT04072354, NCT04092686).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Dropouts due to adverse event

Timepoint 1: 1 day - 2 weeks

Correlation was assumed 0 for the crossover studies (Hopkins 2021, Tsukada 2023)

Timepoint 2: 3 weeks - 13 weeks

No data were available from the unpublished ulotaront studies (i.e., NCT04072354, NCT04092686).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Serious adverse event

Timepoint 1: 1 day - 2 weeks

This outcome was considered rare event, and it was analyzed with a fixed-effects MH method. A correlation of 0 was assumed for crossover studies.

Timepoint 2: 3 weeks - 13 weeks

This outcome was considered rare event, and it was analyzed with a fixed-effects MH method. No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Death

Timepoint 1: 1 day - 2 weeks

This outcome was considered rare event, and it was analyzed with a fixed-effects MH method. A correlation of 0 was used for crossover studies.

Timepoint 2: 3 weeks - 13 weeks

This outcome was considered rare event, and it was analyzed with a fixed-effects MH method.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Any adverse event

Timepoint 1: 1 day - 2 weeks

A correlation of 0 was assumed for crossover studies.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Anticholinergic symptoms

Terms that were considered as reported in the trials: dry mouth (no other relevant anticholinergic side-effects were reported such as urinary retention, constipation, mydriasis or blurred vision)

Timepoint 1: 1 day - 2 weeks

Only data from one study on healthy volunteers were available (Perini 2023)

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Hypotension

Terms that were considered as reported in the trials: hypotension or orthostatic hypotension

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the four trials on acute schizophrenia.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Dizziness

Timepoint 1: 1 day - 2 weeks

A correlation of 0 was assumed for crossover studies.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the four trials on acute schizophrenia.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Nausea or vomiting

Terms that were considered as reported in the trials: nausea, vomiting, emesis

Timepoint 1: 1 day - 2 weeks

A correlation of 0 was assumed for crossover studies.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686). The study NCT04512066 examined ralmitaront while the other trials ulotaront (which is also a 5-HT1A receptor partial agonist).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: QTc prolongation

Terms that were considered as reported in the trials: QTc prolongation above ≥450 msec or an increase of ≥60 msec (any threshold was eligible)

Timepoint 1: 1 day - 2 weeks

A correlation of 0 was assumed for the two crossover studies with reported QTc prolongation.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686). The study NCT04512066 examined ralmitaront while the other trials ulotaront (which is also a 5-HT1A receptor partial agonist).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: QTc interval in msec

Timepoint 1: 1 day - 2 weeks

One crossover study reported data for this outcome (Tsukada 2023). The analysis was adjusted for crossover and was reported for several timepoints within a day. The AUC was calculated and the divided by 24 hours for presentation.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Weight increased

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686) and the study on Parkinson disease psychosis (Isaacson 2023).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Weight in kg

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Hyperprolactinemia

Timepoint 1: 1 day - 2 weeks

Only one data from cossover RCT with assumed correlation of 0 (Hopkins 2021)

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Prolactin levels

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

SD was imputed from Huhn et al 2021. No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Akathisia

Terms considered included: restlessness (when was used to describe akathisia)

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Extrapyramidal symptoms

Terms considered included: any extrapyramidal symptom, no finding in the movement disorder scales, use of anticholinergic medications (when used to treat extrapyramidal symptosm)

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023), and the unpublisshed study on ralmitaront (NCT04512066)

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Anxiety

Timepoint 1: 1 day - 2 weeks

Data were available only from one RCT on healthy volunteers.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Agitation

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Headache

Timepoint 1: 1 day - 2 weeks

Data were available only from one RCT on healthy volunteers.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Sedation

Terms that were considered as reported in the trials: fatigue, sedation, somnolence

Timepoint 1: 1 day - 2 weeks

Data were available only from two RCT on healthy volunteers. Correlation was assumed 0 for the crossover study (Hopkins 2021)

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Insomnia

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data were available from the two unpublished ulotaront trials (i.e., NCT04072354, NCT04092686), the study on Parkinson disease psychosis (Isaacson 2023).

Timepoint 3: > 13 weeks

No data available from RCT.

Summary plot for the side-effects

Secondary outcome: Neurobiological measures relevant relevant to psychosis such as dopaminergic, glutamatergic and serotonergic signalling

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Comparison 2: TAAR1 agonist vs antipsychotic

Primary outcome: Overall symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks (primary timepoint)

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Positive symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Negative symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Depressive symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Cognitive symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Quality of life

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Functioning

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Response to treatment

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Relapse

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Dropouts due to any reason

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Dropouts due to adverse event

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Serious adverse event

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Death

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Any adverse event

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Anticholinergic symptoms

Terms that were considered as reported in the trials: dry mouth (no other relevant anticholinergic side-effects were reported such as urinary retention, constipation, mydriasis or blurred vision)

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Hypotension

Terms that were considered as reported in the trials: hypotension or orthostatic hypotension

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Dizziness

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Nausea or vomiting

Terms that were considered as reported in the trials: nausea, vomiting, emesis

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

It should be noted that the study NCT04512066 examined ralmitaront (which compared to ulotaront is not a partial agonist of the 5-HT1A receptor)

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: QTc prolongation

Terms that were considered as reported in the trials: QTc prolongation above ≥450 msec or an increase of ≥60 msec (any threshold was eligible)

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: QTc interval in msec

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Weight increased

Terms considered included: any weight increase, weight increase >7%

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Weight in kg

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Hyperprolactinemia

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Prolactin levels

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Akathisia

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Exrapyramidal symptoms

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Anxiety

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Agitation

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Headache

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Sedation

Terms that were considered as reported in the trials: fatigue, sedation, somnolence

Timepoint 1: 1 day - 2 weeks

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Secondary outcome: Insomnia

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

Timepoint 3: > 13 weeks

No data available from RCT.

Summary plot for the side-effects

Secondary outcome: Neurobiological measures relevant relevant to psychosis such as dopaminergic, glutamatergic and serotonergic signalling

Timepoint 1: 1 day - 2 weeks

No data available from RCT.

Timepoint 2: 3 weeks - 13 weeks

No data available from RCT.

Timepoint 3: > 13 weeks

No data available from RCT.

Subgroup analyses and meta-regressions

We did not conduct subgroup analyses and meta-regressions for the primary outcome due to the small number of included studies (i.e., 5) that precluded the exploration of potential reasons of heterogeneity.

Descriptive exploration of potential dose-effects

We wanted to further explore the potential dose-effects of ulotaront or ralmitaront on improving overall symptoms in acute patients with schizophrenia, given that their doses were pooled in the analyses mentioned above. For this reason, we caclulated the effect sizes of each of the doses of these drugs compared to placebo (correcting the smaple of placebo as a shared control in a trial), and we plotted them in the figure below. No clear dose-effects can be observed.

*It should be noted that Koblan 2020 was a two-arm flexible dose study, and its effect size is placed in the middle of the range of the administered dose (50mg/d to 75mg/d), yet the median or mean dose in the trial could be different and was not reported. **The study of Isaacson 2023 was not presented here, as it was included participants with Parkinson disease psychosis.

Sensitivity analyses

We did not conduct the following pre-planned sensitivity analyses for the primary outcome due to the small number of included studies (i.e., 5), i.e., 1) restricting the analysis to studies with an overall low risk of bias (no study had an overall low risk of bias) and 2) excluding estimates with imputed values (the N and SD of the ulotaront unpublished studies was imputed.

Reporting bias

We evaluated the potential reporting bias for the primary outcome (overall symptoms in acute psychosis) using the ROB-ME tool.

Results matrix for the primary outcome

Name Diagnosis Sample size Data availability
Isaacson (2023) Parksinon disease psychosis 39
Koblan (2020) Schizophrenia spectrum 245
NCT04072354 (2019) Schizophrenia spectrum 463 ✓ (adult) / ?(adolescent)
NCT04092686 (2019) Schizophrenia spectrum 462
NCT04512066 (2020) Schizophrenia spectrum 287
NCT04825860 (2021) Schizophrenia spectrum 480 ~

✓: A study result is available for inclusion in the meta-analysis.; ~:No study result is available for inclusion in the meta-analysis, for a reason unrelated to the P value, magnitude or direction of the result.; ?: Unclear whether an eligible study result was generated. *NCT04072354 included two parts, i.e., adults (sample size 435) and adolescents (sample size unclear but probably 28; planned 90). It should be noted that all of the other studies included adult populations. **NCT04825860 is an ongoing trial.

Funnel plots and examination of small-study effects

There were no sufficient data (i.e., 5 studies < 10) to examine small-study effects with funnel plots.

Coverage of the search strategy

We conducted a comprehensive search of published and unpublished studies. Although we have not contacted the pharmaceutical companies (Hoffman-Roche for ralmitaront, and Sunovion/Sumitomo for ulotaront), it is not expected that any study was not identified in the search, as all of the trials were very recently published, and they should all have been registered.

ROB-ME evaluation

There were no missing results in the studies identified (except for one small trial in adolescnets which data should not have an impact on the findings).There wre also no circumstances indicating potential for missing studies, and no clear patter of the results indicate potential missing studies (although funnel plots could not have been conducted due to the small number of studies). The same evaluation is relevant for both the comparisons of TAAR1 agonists vs. placebo and TAAR1 agonsits vs. antipsychotics. Therefore, there was assigned a low risk of bias in reporting bias.

Summary of the evidence on the primary outcome from the human studies

Summary of the evidence tables

The primary outcome was efficacy in reducing overall symptoms in acutely ill patients with psychosis, i.e., available data for adults with Parkinson disease psychosis and schizophrenia spectrum (analyzed separately). There were available data for two comparisons, i.e., TAAR1 agonists (ulotaront or ralmitaront) vs. placebo, and TAAR1 agonist (ralmitaront) vs. antipsychotics (risperidone). The summary of the evidence on the primary outcome for the above mentioned populations and comparisons are reported below.

Source of evidence   Summary of the association   Bias due to study limitations Bias due to reporting bias Bias due to indirectedness   Bias due to other reasons
TAAR1 agonist. vs placebo in adults with Parkinson disease psychosis n=1, k=37, SMD= -0.28, 95%CI: -0.95, 0.38 100% of the studies had an overall high risk of bias (due to missing outcome data, unclear direction and impact on the findings) Low risk of reporting bias Data available only for ulotaront. No other clear indication of indirectness in terms of population, interventions and outcomes No clear indication of other biases
TAAR1 agonist. vs placebo in adults with schizophrenia spectrum disorder n=4, k=1291, SMD=0.15, 95%CI: -0.05, 0.34, tau2=0.024 All studies had an overall low risk of bias (some concerns due to missing outcome data, unclear direction and impact on the findings - potentially minimal) Low risk of reporting bias Data available only for ulotaront (3 studies) and ralmitaront (1 study).No other clear indication of indirectness in terms of population, interventions and outcomes The phase III ulotaront trials conducted during COVID-19, which could be associated with factors assocaited with increased placebo effects and smaller effect sizes. No clear dose-effects.
TAAR1 agonist. vs other antipsychotics in adults with schizophrenia spectrum disorder n=1, k=156, SMD=-0.53, 95%CI: -0.86, -0.20 One study with an overall low risk of bias (some concerns due to missing outcome data, unclear direction and impact on the findings - potentially minimal) Low risk of reporting bias Data available only for ralmitaront (no data for ulotaront) and risperidone (no data for other antipsychotics). No other clear indication of indirectness in terms of population and outcomes No clear indication of other biases

k: number of studies, n: number of participants, I2: I-squared, SMD>0 indicates a favourable effect for the TAAR1 agonist. It should be noted that there is low confidence evidence that studies with high risk of bias in misisng outocme data may underestimate the effects (PMID: 37939743).

GRADE approach in evaluating the confidence in the evidence

What are the effects of TAAR1 agonists versus placebo on overall symptoms in adults with acute schizophrenia spectrm disorder?

TAAR1 agonists may have little to no effect compared to placebo on overall symptoms in acutely ill adults with schizophrenia spectrum disorder (SMD=0.15, 95%CI: -0.05, 0.34). Specifically, the confidence in the evidence was low due to some concerns in imprecision (95%CI crossed line of no differences and 0.1) and some concerns in heterogeneity (although could not be well estimated due to the small number of studies).

What are the effects of TAAR1 agonists versus antipsychotics on overall symptoms in adults with acute schizophrenia spectrm disorder?

TAAR1 agonists may be less efficacious with a medium effect size compared to other antipsychotics in improving overall symptoms in acutely ill adults with schizophrenia spectrum disorder (SMD=-0.53, 95%CI: -0.86, -0.20). The confidence in the evidence was low due to some concerns in imprecision (although 95%CI did not cross the range of equivalence, the sample size was small <800 participants) and some concerns in indirectness (no data ulotaront and other antipsychotics).

What are the effects of TAAR1 agonists versus placebo on overall symptoms in adults with Parkinson disease psychosis?

TAAR1 agonists may have little to no effect compared to placebo on overall symptoms in acutely ill adults with Parkinson disease psychosis (SMD=-0.28, 95%CI: -0.95, 0.38) and the evidence is very uncertain. Specifically, the confidence in the evidence was very low due to major concerns in imprecision (95%CI crossed beyond SMD -0.1 and 0.1, and the sample size was very small <800 participants), and some concerns in the risk of bias (study with a high risk of bias).